Muscle degeneration without mechanical injury in sarcoglycan deficiency

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Abstract
In humans, mutations in the genes encoding components of the dystrophin–glycoprotein complex cause muscular dystrophy. Specifically, primary mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan have been identified in humans with limb-girdle muscular dystrophy. Mice lacking γ-sarcoglycan develop progressive muscular dystrophy similar to human muscular dystrophy. Without γ-sarcoglycan, β- and δ-sarcoglycan are unstable at the muscle membrane and α-sarcoglycan is severely reduced. The expression and localization of dystrophin, dystroglycan, and laminin-α2, a mechanical link between the actin cytoskeleton and the extracellular matrix, appears unaffected by the loss of sarcoglycan. We assessed the functional integrity of this mechanical link and found that isolated muscles lacking γ-sarcoglycan showed normal resistance to mechanical strain induced by eccentric muscle contraction. Sarcoglycan-deficient muscles also showed normal peak isometric and tetanic force generation. Furthermore, there was no evidence for contraction-induced injury in mice lacking γ-sarcoglycan that were subjected to an extended, rigorous exercise regimen. These data demonstrate that mechanical weakness and contraction-induced muscle injury are not required for muscle degeneration and the dystrophic process. Thus, a nonmechanical mechanism, perhaps involving some unknown signaling function, likely is responsible for muscular dystrophy where sarcoglycan is deficient.